Contraception system and method

ABSTRACT

A method of contraception is disclosed which comprises a two-stage protocol. In the first stage, an estrogenic compound in a first composition is administered daily as the sole contraceptively active substance to a human female from about Day 2 to about Day 7 of her menstrual cycle, where Day 1 is the first day of menses. The second stage of the protocol occurs immediately thereafter during which at least one follow-up composition containing a progestin is administered daily to the same human female. The follow-up composition can contain a progestin as the sole contraceptively active ingredient, or can contain a combination of an estrogenic compound with a progestin in different weight ratios. A drug delivery system containing daily dosage units is also described.

.Iadd.This is a continuation of application Ser. No. 07/875,277, filedApr. 28, 1992. .Iaddend.

TECHNICAL FIELD

This invention relates to the practice of contraception utilizing atwo-stage protocol that minimizes this incidence of breakthroughbleeding.

Background of the Invention

Oral contraceptives first became available in the early 1960's. Throughcontinued research, new lower-dose estrogen products of higheffectiveness have been developed. The oral administration ofcombination-type preparations containing estrogens and progestins hasbeen known for some time. The administration of purely sequentialpreparations to mimic the normal 28-day menstrual cycle of the patientis also known. In such instances, an estrogen is administered at a highdosage, in the absence of a progestin, over a period of fourteen tosixteen days, thereafter the estrogen is administered at the same highdosage in combination with a relatively high amount of progestin over aperiod of five to six days, and during the next seven to eight daysthere is no administration of estrogen or progestin. Physician's DeskReference, 30th edition, pages 1026, 1127 and 1532, respectively (1976).

It has more recently been published in Goodman and Gilman, ThePharmacological Basis of Therapeutics, 7th edition, pages 1430-1436(1985), that sequential combination administration includes the usage ofan estrogen at a high dosage, in the absence of a progestin, over aperiod of seven days, thereafter the estrogen is administered at thesame high dosage in combination with a relatively high amount of sprogestin over a period of 15 days, and during the next six days thereis no administration of estrogen or progestin.

In Vorys U.S. Pat. Nos. 4,292,315 and 4,372,951, various sequential andcombination oral contraceptive delivery systems are disclosed. All ofthe systems described in the patents to Vorys comprise an early 7-dayperiod in which no exogenous steroids are administered, followed by a7-day period in which a pharmacologically low dose of an unopposedestrogen or progestin steroid is administered daily, followed by anarbitrary 14-day period in which various combinations of estrogen andprogestin are administered daily in various pharmacological dosages.None of the systems described in Vorys utilize the administration of anunopposed estrogen during the initial seven days of the menstrual cycle.

Biphasic and triphasic oral contraceptive combinations have beendescribed in Pasquale U.S. Pat. Nos. 4,530,839; 4,544,554; and4,628,051. The described biphasic and triphasic oral contraceptivesystems do not include the administration of an unopposed estrogeniccompound during the first seven days of the menstrual cycle. In thebiphasic combination type oral contraceptives, a combination of anestrogen and a low dosage of a progestin is first administered for 10-12days, Subsequently, a combination of the same dosage of estrogen and anincreased progestin dosage is administered for the remaining 9-11 daysof a 21-day regimen. The biphasic systems were developed in an effort toreduce dosage and keep bleeding patterns at an acceptable level.

In the triphasic oral contraceptive regimen, an estrogen dosage is keptconstant throughout the 21-day regimen while the progestin dosage isgradually increased is successive steps. Thus, the 21-day regimencomprises an initial 7-day period in which a daily dose of a combinationof an estrogenic compound together with a low dosage of a progestin isadministered; followed by a 7-day period in which a daily dosage of anestrogenic compound together with a moderate progestin dosage isadministered; followed by a terminal 7-day period in which a dailydosage of an estrogenically effective compound together with a high doseof an progestin is administered to a human female. This regimen is thenfollowed by a 7-day period in which no hormone is given.

A disadvantage of the above-described oral contraceptive systems is thatthere often occurs an incidence of breakthrough bleeding and spotting.Additionally, there is a risk of escaped ovulation or pregnancy,especially if a daily tablet is missed during the cycle. Chowdhury etal., Contraception, 22:241-247 (1980); Molloy et al., Brit. Med. J.290:1474-1473 (1985).

SUMMARY OF THE INVENTION

The present invention relates to a two-stage oral contraceptive systemin which an unopposed estrogenic compound is administered during aterminal portion of the first 7-day segment of the menstrual cycle,counting as Day 1 the onset of menses. In the contemplated methodaspect, an initial composition containing an estrogenic compound as thesole contraceptively active ingredient is administered during theterminal portion of the first 7-day segment of the menstrual cycle,preferably from about Day 2 to about Day 7, inclusive, of the menstrualcycle, at a daily dosage equivalent in estrogenic activity to about 0.01to about 0.04 mg of 17-alpha-ethinyl estradiol, to a human female ofchild-bearing age for contraception purposes. Following this initialadministration of a relatively small dosage of an unopposed estrogeniccompound, the second stage of the contemplated contraceptive system iscommenced. In the second stage, a daily administration of a follow-upcomposition containing a progestin, alone or in combination with anestrogenic compound, is continued to about Day 28 of the menstrualcycle.

The method of contraception of the present invention contemplates thatthe follow-up composition, administered during Days 7 to 28 of themenstrual cycle preferably contains a combination of an estrogeniccompound and a progestin. The composition administered during the secondstage can be a uniphasic, biphasic or triphasic combination oralcontraceptive system.

In the present drug delivery system at least 24 separate dosage unitsare included for successive daily oral administration. Preferably, atleast three initial dosage units contain a pharmacologically activedaily dosage amount of an unopposed estrogenic compound, and theremainder each contain a pharmacologically active daily dosage amount ofa composition containing a progestin as aforesaid.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

The present invention provides a two-stage protocol which is utilized asa method of contraception in a human Female while minimizing theincidence of breakthrough bleeding. In the first stage of this protocol,a composition containing an estrogenic compound as the solecontraceptively active ingredient is administered during a terminalportion of the first 7-day segment of the menstrual cycle, preferablyfrom Day 4 to Day 7 of the menstrual cycle. In the second stage of theprotocol commencing immediately after the first stage, a follow-up dailydosage of a composition containing a progestin is administered throughDay 28 of the menstrual cycle. Throughout the present specification andclaims, Day 1 of the menstrual cycle is defined as the day on whichonset of menses is noted.

This follow-up progestin-containing composition can be:

(1) a composition containing an unopposed progestin;

(2) a combination of an estrogenic compound and a progestin;

(3) a biphasic oral contraceptive in which one dosage of a combinationof an estrogenic compound and a progestin is administered daily forabout 10 days of the menstrual cycle, and followed by administration ofa follow-up dosage of an estrogenic compound and a progestin, which isadministered daily for the remainder of the menstrual cycle; or

(4) a triphasic oral contraceptive, in which three group of seven dailydosages each, are administered consecutively in a predeterminedsequence. The dosage units in each such group contain a composition ofan estrogenic compound and a progestin; however all three groups do notcontain the same weight ratio of estrogenic compound and progestin.

Estrogenic compounds, as the term is used herein, includes hormones aswell as other compounds that exhibit estrogenic activity. That is, anestrogenic compound is a compound having the ability to elicit aphysiological response similar to that normally produced by endogenousestrogen in a human female, such as inhibition of follicle stimulatinghormone (FSH) secretion. Illustrative such compounds include17-alpha-ethinyl estradiol 3-methylether, mestranol, 17-beta-estradiol,17-alpha-ethinyl estradiol, and the like.

Progestins utilizable in the present invention include progestrone andits derivatives such as, for example, 17-hydroxy progestrone esters and19-nor-17-hydroxy progestrone esters, 17-alpha-ethinyl testosterone,17-alpha-ethinyl-19-nortestosterone and derivatives thereof,norethindrone, norgestrel, norgestamate. Desorgestrel, andD-17-beta-acetoxy-17-beta-ethyl17-alpha-ethinyl-gon-4-en-3-one oxime.The preferred progestins are norethindrone, D-norgestrel andD-17-beta-acetoxy-13-beta-ethyl-17-alpha-ethinyl-gon-4-en-3-one oxime.

A preferred dosage of an estrogenic compound in the present invention isa dosage that is equivalent in estrogenic activity to about 0.01 toabout 0.04 milligrams (mg) of 17-alpha-ethinyl estradiol.

Preferred dosages for the progestin of the present invention are about0.5 to about 1.0 mg.

In spontaneous menstrual cycles, the dominant follicle is recruitedduring the first six days of the menstrual cycle, where Day 1 is countedas the first day of bleeding. During this period of time, the FSH levelis slightly elevated, and then decreases to peak again at mid-cycle atthe time of ovulation. The present invention utilizes the fact thatestrogen suppresses FSH levels. Thus, by administration of estrogenduring the first seven days of the menstrual cycle, the follicularperiod, escape ovulation is less likely to occur if a dosage unit ismissed.

Estrogen administration at this early stage of the menstrual cycle alsoprevents recruitment of the dominant follicle and thus allows areduction in the dose of the estrogen and progestin in the combinationoral contraceptive needed between Days 7 and 28 of the menstrual cycleto prevent conception. Additionally, estrogens stimulate progesteronereceptor sites. By simulation of progesterone receptors early in themenstrual cycle, estrogen administration allows a reduction in theincidence of intermenstrual bleeding. That is, breakthrough bleeding andspotting are minimized with the low-dose oral contraceptives of thepresent invention.

Following the period of unopposed estrogen administration during thefollicular period of the menstrual cycle, a second stage ofadministration comprising a 21-day regime of daily dosages of a standardoral contraceptive composition is followed. This second stage periodcomprises the administration of successive daily dosages of aprogestin-containing composition.

Illustrative of the second stage of the method of the present inventionare oral contraceptive compositions which contain one or morecombination dosages of an estrogenic compound and a progestin, or aprogestin alone. Such following-up combinations of an estrogeniccompound and a progestin can constitute a uniphasic, biphasic ortriphasic oral contraceptive system.

In the uniphasic system, a single dosage of a combination of anestrogenic compound and a progestin is administered daily for the 21days of the second stage of the method of the present invention. In apreferred uniphasic system, a daily dosage unit containing 0.035 mgethinyl estradiol and 0.5 mg norethindrone is administered.

In the biphasic system, two different dosage levels of an estrogeniccompound and a progestin are administered, one level for about 7 toabout 10 days of the 21-day regimen and the second dosage level for theremainder of the menstrual cycle.

In one preferred system, plural follow-up compositions are administeredin sequence. The daily dosage of the estrogenic compound issubstantially the same in all administered follow-up compositions, andthe daily dosage of the progestin is greater in each successivefollow-up composition. In a particularly preferred embodiment, a dailydosage of 0.035 mg ethinyl estradiol and 0.5 mg of norethindrone isadministered to a female for about 7 to about 10 days, followedimmediately in sequence by a daily dosage of 0.035 mg ethinyl estradioland 1.0 mg norethindrone for the remainder of the menstrual cycle.

In the triphasic system, administration is divided into threeapproximately 7-day periods of daily oral contraceptive administration;the daily dosage level of the combination of an estrogenic compound anda progestin varies between successive approximately 7-day regimenperiods. In the triphasic system, the three respective dosages can bedifferent from each other or can be similar to each other during thefirst and third 7-day periods of administration.

In a particularly preferred embodiments, a daily dosage of 0.035 mgethinyl estradiol and 0.5 mg norethindrone is administered to a femalefor about seven days, followed immediately in sequence by the dailyadministration of 0.035 mg ethinyl estradiol and 0.75 mg norethindronefor the next seven days, and then followed immediately in sequence bythe daily administration of 0.035 mg ethinyl estradiol and 1.0 mgnorethindrone for the remaining seven days of the menstrual cycle.

In a second preferred system of contraception, plural follow-upcompositions are administered in sequence in which the daily dosage ofthe estrogenic compound is substantially the same in all administeredfollow-up compositions and in which the daily dosage of progestin insuccessive follow-up compositions first increases to a value greaterthan the level of progestin first administered and then decreases to alevel corresponding to the same value as that of the progestin firstadministered as the daily progestin dosage. In a particularly preferredembodiment, a daily dosage of 0.035 mg ethinyl estradiol and 0.5 mgnorethindrone is administered for about seven days, immediately followedby a daily administration of a dosage of 0.035 mg ethinyl estradiol and1.0 mg norethindrone for about the next seven days, and then immediatelyfollowed by a daily administration of a dosage of 0.035 mg ethinylestradiol and 0.5 mg norethindrone for the remaining seven days of themenstrual cycle.

The estrogen and progestin components in the second stage of the presentinvention are preferably administered admixed together, but they canalso be administered separately. In general, the effective agents arecompounded together to form a single dosage unit. Preferred dosage unitsare tablets or pills.

In the dosage units, the effective contraceptive agents are combinedwith the excipients, vehicles, and pharmacologically acceptable carrierscommonly employed by one of ordinary skill in the preparation ofpharmaceuticals in accordance with generally accepted pharmaceuticalpractices. Exemplary pharmaceutically acceptable carriers include cornstarch, lactose, dicalcium phosphate, thickeners such as tragacanth andmethylcellulose U. S. P., Freely divided SiO₂, polyvinylpyrrolidone,magnesium stearate and the like. Additionally, a solid carrier caninclude biodegradable and non-biodegradable polymers and polypeptidecarriers. Antioxidants, such as methylparaben and propylparaben can bepresent, as can sweeteners such as cane or beet sugar, sodium saccharin,sodium cyclamate and the dipeptide methylester sweeteners commerciallyavailable under the trademark NUTRA SWEET (aspartame) by the NutrasweetCompany (North Chicago, Ill.). Among the various oral dosage forms,tablets, capsules, and pills are particularly preferred.

A drug delivery system embodying the present invention contains apharmaceutical package having at least 24 active dosage units arrangedsequentially therein. Preferably, the pharmaceutical package contains 28dosage units, including placebo units. This drug delivery system has atleast four dosage units for the first stage of the method of the presentinvention and 21 dosage units for the second stage thereof. A singledosage unit is a daily dosage unit to be taken each day over the periodof administration.

In a particularly preferred embodiment, the drug delivery system of thepresent invention contains 28 tablets. The first set of tablets in eachsequence contains a placebo, the next four or five tablets in thesequence contain a composition of an unopposed estrogenic compound, andthe remaining 21 tablets in the sequence contain a desired follow-uporal contraceptive composition as described hereinabove.

In a preferred embodiment the twenty one follow-up dosage units eachcontain substantially the same daily dosage of an estrogenic compoundand a progestin.

In an alternate preferred embodiment the twenty one follow-up dosageunits comprise a first group of 10 dosage units that each contain afirst contraceptively effective daily dosage of an estrogenic compoundand a progestin, and a second group of 11 dosage units that each containa second follow-up contraceptively effective dosage of a progestin andan estrogenic compound.

In another alternate preferred embodiment, the twenty-one follow-updosage units comprise three consecutive groups of about seven dosageunits each, where each group contains contraceptively effective dailydosage units of an estrogenic compound and a progestin. The estrogeniccompound and progestin in each individual group are present insubstantially the same weight ratio, with the proviso that the weightratios of the estrogenic compound to the progestin are different for therespective dosage units that constitute consecutively administeredgroups.

Certain specific examples are provided hereinbelow for purposes ofillustration only and are not to be taken as limiting.

EXAMPLE 1 Estrongenic Compound Plus Uniphasic Contraceptive Regimen

A placebo tablet is administered to a menstruating human female for thefirst two days of the menstrual cycle, at Day 1 is the first day ofbleeding. On Days 3 to 7, inclusive, 0.02 mg of ethinyl estradiol isadministered daily. From Day 8 to the end of the menstrual cycle at Day28, inclusive, a daily dosage of 0.035 mg of ethinyl estradiol togetherwith 0.5 mg of norethindrone is administered. This regimen isillustrated in TABLE I.

                  TABLE I                                                         ______________________________________                                        Contraceptive Regimen                                                         ______________________________________                                        Day       1       2     3     4   5     6   7                                 Composition                                                                             P       P     E     E   E     E   E                                 Day       8       9     10    11  12    13  14                                Composition                                                                             C       C     C     C   C     C   C                                 Day       15      16    17    18  19    20  21                                Composition                                                                             C       C     C     C   C     C   C                                 Day       22      23    24    25  26    27  28                                Composition                                                                             C       C     C     C   C     C   C                                 ______________________________________                                         Day = Day of the Menstrual Cycle: Day 1 as the first day of bleeding.         Composition = the active ingredient(s) present in a daily dosage unit         taken on the respective day of the menstrual cycle.                           P = placebo, contains no contraceptively active ingredients.                  E = 0.02 mg ethinyl estradiol.                                                C = combination containing 0.035 mg ethinyl estradiol and 0.5 mg              norethindrone.                                                           

EXAMPLE 2 Estrogenic Compound Plus Uniphasic Contraceptive Regimen

A placebo tablet is administered to a menstruating human female for thefirst two days of menstrual cycle, where Day 1 is the first day ofbleeding. On Days 3 to 7, inclusive, 0.04 mg of ethinyl estradiol isadministered daily. From Day 8 to the end of her menstrual cycle at Day28, inclusive, a daily dosage of 0.035 mg ethinyl estradiol togetherwith 0.5 mg norethindrone is administered. This regimen is illustratedin TABLE II.

                  TABLE II                                                        ______________________________________                                        Contraceptive Regimen                                                         ______________________________________                                        Day       1       2     3     4   5     6   7                                 Composition                                                                             P       P     E     E   E     E   E                                 Day       8       9     10    11  12    13  14                                Composition                                                                             C       C     C     C   C     C   C                                 Day       15      16    17    18  19    20  21                                Composition                                                                             C       C     C     C   C     C   C                                 Day       22      23    24    25  26    27  28                                Composition                                                                             C       C     C     C   C     C   C                                 ______________________________________                                         Day = Day of the Menstrual Cycle: Day 1 is the first day of bleeding.         Composition = the active ingredient(s) present in a daily dosage unit         taken on the respective day of the menstrual cycle.                           P = placebo, contains no contraceptively active ingredient.                   E = 0.04 mg ethinyl estradiol.                                                C = combination containing 0.035 mg ethinyl estradiol and 0.5 mg              norethindrone.                                                           

EXAMPLE 3 Estrogenic Compound Plus Triphasic Contraceptive Regimen

A placebo dosage is administered to a menstruating human female for thefirst two days of her menstrual cycle, where Day 1 is the first day ofbleeding. On Days 3 to 7, inclusive, a daily dosage of about 0.02 mg toabout 0.04 mg of ethinyl estradiol is administered. From Day 8 to Day14, inclusive, a daily dosage of 0.035 mg ethinyl estradiol togetherwith 0.5 mg norethindrone is administered. From Day 15 to Day 21,inclusive, 0.035 mg of ethinyl estradiol together with 0.75 mgnorethindrone is administered daily. Following this, a third phase isbegun where from Day 22 to Day 28, inclusive, a daily dosage of 0.035 mgethinyl estradiol together with 1.0 mg of norethindrone is administered.This regimen is illustrated in TABLE III.

                  TABLE III                                                       ______________________________________                                        Contraceptive Regimen                                                         ______________________________________                                        Day       1       2     3     4   5     6   7                                 Composition                                                                             P       P     E     E   E     E   E                                 Day       8       9     10    11  12    13  14                                Composition                                                                             C1      C1    C1    C1  C1    C1  C1                                Day       15      16    17    18  19    20  21                                Composition                                                                             C2      C2    C2    C2  C2    C2  C2                                Day       22      23    24    25  26    27  28                                Composition                                                                             C3      C3    C3    C3  C3    C3  C3                                ______________________________________                                         Day = Day of the Menstrual Cycle: Day 1 is the first day of bleeding.         Composition = the active ingredient(s) present in a daily dosage unit         taken on the respective day of the menstrual cycle.                           P = placebo, contains no contraceptively active ingredients.                  E = about 0.02 to about 0.04 mg ethenyl estradiol.                            C1 = 0.035 mg ethinyl estradiol and 0.5 mg norethindrone.                     C2 = 0.035 mg ethinyl estradiol and 0.75 mg norethindrone.                    C3 = 0.035 mg ethinyl estradiol and 1.0 mg norethindrone.                

The foregoing specification, including the specific embodiment andexamples, is intended to be illustrative of the present invention and isnot to be takes as limiting. Numerous other variations and modificationscan be effective without departing from true spirit and scope of thepresent invention.

I claim:
 1. A method of contraception .Iadd.by suppressing recruitmentof the dominant follicle .Iaddend.comprising:(a) administering.Iadd.orally .Iaddend.to a human female of child-bearing age, daily from. .about Day 2 to about.!. .Iadd.Day 3 or Day 4 through .Iaddend.Day 7of her menstrual cycle, wherein Day 1 is the first day of menses, afirst composition containing as sole contraceptively active ingredientan estrogenic compound at a daily dosage equivalent in estrogenicactivity in the range of about 0.01 to about 0.04 milligrams of17-alpha-ethinyl estradiol; and thereafter (b) administering.Iadd.orally .Iaddend.to said female, daily through Day 28 of hermenstrual cycle, at least one follow-up composition containing acontraceptively effective daily dosage of a progestin.
 2. The method ofcontraception according to claim 1, wherein said follow-up compositioncontains a progestin as sole contraceptively active ingredient.
 3. Themethod of contraception according to claim 1, wherein said follow-upcomposition comprises contraceptively effective amounts of an estrogeniccompound and a progestin.
 4. The method of contraception according toclaim 1 wherein said estrogenic compound is ethinyl estradiol.
 5. Themethod of contraception according to claim 1 wherein said estrogeniccompound is mestranol.
 6. The method of contraception according to claim1 wherein said estrogenic compound is 17-beta-estradiol.
 7. The methodof contraception according to claim 1 wherein said follow-up compositioncontains norethindrone at a daily dosage in the range of about 0.5 mg toabout 1.0 mg.
 8. The method of contraception according to claim 1,wherein said progestin is D-norgestrel.
 9. The method of contraceptionaccording to claim 1, wherein said progestin isD-17-beta-acetoxy-13-beta-ethyl-17-alpha-ethinyl-gon-4-en-3-one oxime.10. The method of contraception according to claim 1, wherein saidprogestin is a 19-nor-17-hydroxy progesterone ester.
 11. The method ofcontraception according to claim 1 wherein said estrogenic compound isethinyl estradiol and said progestin is norethindrone.
 12. The method ofcontraception according to claim 1 wherein said estrogenic compound ismestranol and said progestin is D-norgestrel.
 13. The method ofcontraception according to claim 1 wherein plural follow-up compositionsare administered in sequence, wherein the daily dosage of the estrogeniccompound is substantially the same in all administered follow-upcompositions, and wherein the daily dosage of progestin is greater ineach successive follow-up composition.
 14. The method of contraceptionaccording to claim 13 wherein said estrogenic compound is ethinylestradiol and said progestin is norethindrone.
 15. The method ofcontraception according to claim 14 wherein said daily dosage of ethinylestradiol is about 0.035 mg.
 16. The method of contraception accordingto claim 1 wherein plural follow-up compositions are administered insequence, wherein the daily dosage of the estrogenic compound issubstantially the same in all administered follow-up compositions; andwherein the daily dosage or progestin in successive follow-upcompositions first increases to a value greater than the daily progestindosage first administered and then decreases to the same value as thedaily progestin dosage first administered.
 17. The method ofcontraception according to claim 16 wherein said daily dosage of ethinylestradiol is 0.035 mg.
 18. A drug delivery system constituted by atleast 24 separate daily dosage units, adapted for oral administrationand comprising:at least four .Iadd.but not more than five.Iaddend.initial dosage units each containing as the solecontraceptively active ingredient the same contraceptively effectivedaily dosage of an estrogenic compound; followed by twenty-one follow-updosage units each containing a contraceptively effective daily dosage ofa progestin.
 19. The drug delivery system according to claim 18, whereinaid twenty-one follow-up dosage units each contain substantially thesame daily dosage of a progestin.
 20. The drug delivery system accordingto claim 18, wherein said twenty-one follow-up dosage units each containsubstantially the same daily dosage of an estrogenic compound and aprogestin.
 21. The drug delivery system according to claim 18 whereinsaid twenty-one follow-up dosage units comprise a first group of 10dosage units that each contain a first contraceptively effective dailydosage of an estrogenic compound and a progestin, and a second group of11 dosage units that each contain a follow-up contraceptively effectivedaily dosage of a progestin and an estrogenic compound.
 22. The drugdelivery system according to claim 18 wherein said follow-up dosageunits comprise three consecutive groups of about seven dosage unitseach, and wherein each of said groups individually comprisescontraceptively effective daily dosage units of an estrogenic compoundand a progestin present in substantially the same weight ratio, with theproviso that the weight ratios of said estrogenic compound to saidprogestin are different for the respective dosage units that constituteconsecutively administered groups.
 23. The drug delivery systemaccording to claim 22 wherein the weight ratio of said estrogeniccompound to said progestin is substantially the same in the first andthe third consecutive groups of dosage units.
 24. The drug deliverysystem according to claim 18 wherein said estrogenic compound present insaid initial dosage units is ethinyl estradiol.
 25. The group deliverysystem according to claim 18 wherein said estrogenic compound present insaid initial dosage units is mestranol.
 26. The drug delivery systemaccording to claim 18 wherein said estrogenic compound present in saidinitial dosage units is 17-beta-estradiol.
 27. The drug delivery systemaccording to claim 18, wherein said progestin is norethindrone.
 28. Thedrug delivery system according to claim 18 wherein said progestin isD-norgestrel.